Quinolone neuropeptide S receptor antagonists

ABSTRACT

The present invention is directed to quinolone compounds which are antagonists of neuropeptide S receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which the neuropeptide S receptor is involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the neuropeptide S receptor is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2009/063030, filed Nov. 3, 2009, whichclaims priority under 35 U.S.C. §119(e) from U.S. Ser. No. 61/199,190,filed Nov. 13, 2008.

BACKGROUND OF THE INVENTION

Neuropeptide S(NPS) is an endogenous brain protein, which is believed toaffect arousal, wakefulness, propensity for movement, asthma and someallergic responses, stress associated with several anxiety disorders andother physiological functions. Neuropeptide S is the endogenous ligandfor the Neuropeptide S receptor (NPSR), which has also been referred toas TGR23 and vasopressin receptor-related receptor 1 (VRR1). TheNeuropeptide S receptor is expressed in certain regions of the brainknown to be involved in anxiety (e.g., the amygdala, thalamus andhypothalamic regions) and administration of NPS to rodents can causeincreased locomotion and anxiolytic effects.

Neuropeptide S receptors are found in the mammalian brain and may havenumerous implications in pathologies such as depression; anxiety;addictions; obsessive compulsive disorder; affective neurosis;depressive neurosis; anxiety neurosis; dysthymic disorder; behaviourdisorder; mood disorder; sexual dysfunction; psychosexual dysfunction;sex disorder; schizophrenia; manic depression; delirium; dementia;severe mental retardation and dyskinesias such as Huntington's diseaseand Tourette syndrome; eating disorders such as anorexia, bulimia,cachexia, dysregulated appetite control; obesity; addictive feedingbehaviors; binge/purge feeding behaviors; cardiovascular diseases;diabetes; appetite, taste, eating or drinking disorders; emesis,vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumour/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; disturbed biological andcircadian rhythms; vigilance; sleep disturbances associated withdiseases such as neurological disorders, neuropathic pain and restlessleg syndrome; heart and lung diseases, acute and congestive heartfailure; hypotension; hypertension; urinary retention; osteoporosis;angina pectoris; myocardinal infarction; ischemic or haemorrhagicstroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatichypertrophy; chronic renal failure; renal disease; impaired glucosetolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain such as hyperalgesia, causalgia, and allodynia;acute pain; burn pain; atypical facial pain; neuropathic pain; backpain; complex regional pain syndrome I and II; arthritic pain; sportsinjury pain; pain related to infection e.g. HIV, post-chemotherapy pain;post-stroke pain; post-operative pain; neuralgia; conditions associatedwith visceral pain such as irritable bowel syndrome, and angina; urinarybladder incontinence e.g. urge incontinence; tolerance to narcotics orwithdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy;insomnia; parasomnia; jet lag syndrome; and neurodegenerative disordersincluding nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders and otherdiseases related to general neuropeptide S system dysfunction.

SUMMARY OF THE INVENTION

The present invention is directed to quinolone compounds which areantagonists of the neuropeptide S receptor, and which are useful in thetreatment or prevention of neurological and psychiatric disorders anddiseases in which neuropeptide S receptors are involved. The inventionis also directed to pharmaceutical compositions comprising thesecompounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which the neuropeptide Sreceptor is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   R¹ is hydrogen or C₁₋₆alkyl, which is unsubstituted or substituted    with —O—C₁₋₆alkyl;-   R² is —C₀₋₆alkyl, which is substituted with one or more substituents    selected from R⁴,    -   wherein R⁴ is selected from the group consisting of:    -   (1) —C₁₋₆alkyl, where the alkyl is unsubstituted or substituted        with one or more substituents selected from R¹³,    -   (2) —C₃₋₈cycloalkyl, where the cycloalkyl is unsubstituted or        substituted with one or more substituents selected from R¹³, or        where the cycloalkyl may be fused to a phenyl, where the phenyl        is unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (3) —C₃₋₈cycloalkoxyl, where the cycloalkoxyl is unsubstituted        or substituted with one or more substituents selected from R¹³,        or where the cycloalkyl may be fused to a phenyl, where the        phenyl is unsubstituted or substituted with one or more        substituents selected from R¹³,    -   (4) -phenyl or -napthyl, where the phenyl or naphthyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (5) -heterocycle, where the heterocycle is unsubstituted or        substituted with one or more substituents selected from R¹³,    -   (6) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected        from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹³,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹³,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹³,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹³,        -   (f) phenyl, which is unsubstituted or substituted with R¹³,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R¹³;-   R³ is selected from the group consisting of:    -   (1) —C₁₋₆alkyl, where the alkyl is unsubstituted or substituted        with one or more substituents selected from R¹³,    -   (2) —C₃₋₆cycloalkyl, where the cycloalkyl is unsubstituted or        substituted with one or more substituents selected from R¹³,    -   (3) -phenyl or -napthyl, where the phenyl or naphthyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (4) -heterocycle, where the heterocycle is unsubstituted or        substituted with one or more substituents selected from R¹³,    -   (5) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected        from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹³,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹³;        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹³,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹³;        -   (f) phenyl, which is unsubstituted or substituted with R¹³,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R¹³;-   R¹³ is selected from the group consisting of:    -   (1) halogen,    -   (2) hydroxyl,    -   (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R¹⁴,    -   (4) —O_(n)—(C₁₋₃)perfluoroalkyl,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (10) —(C═O)_(m)—NR¹⁵R¹⁶, where R¹⁵ and R¹⁶ are independently        selected from hydrogen and —C₁₋₆alkyl, which is unsubstituted or        substituted with phenyl,    -   (11) —S(O)₂—NR¹⁵R¹⁶;    -   (12) —S(O)_(T)R¹², where q is 0, 1 or 2 and where R¹² is        —C₁₋₆alkyl, which is unsubstituted or substituted with phenyl;    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;-   R¹⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH—C₁₋₆alkyl,    -   (8) phenyl,    -   (9) heterocycle,    -   (10) —CO₂H, and    -   (11)—CN;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein R¹ ishydrogen or methyl. An embodiment of the present invention includescompounds wherein R¹ is hydrogen. An embodiment of the present inventionincludes compounds wherein R¹ is methyl.

An embodiment of the present invention includes compounds wherein R² isselected from the group consisting of:

-   -   (1) tetralone,    -   (2) —CH₂-cyclohexyl, where the cyclohexyl is unsubstituted or        substituted with one or more substituents selected from R¹³,    -   (3) —CH₂-morpholinyl, where the morpholinyl is unsubstituted or        substituted with one or more substituents selected from R¹³, and    -   (4) —CH₂—CH-(phenyl)heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³.

An embodiment of the present invention includes compounds wherein R³ isselected from the group consisting of:

-   -   (1) —C₁₋₆alkyl, where the alkyl is unsubstituted or substituted        with one or more substituents selected from —C₃₋₆cycloalkyl and        phenyl, where the cycloalkyl and phenyl are independently        unsubstituted or substituted with one or more substituents        selected from the group consisting of:        -   (a) halogen,        -   (b) hydroxyl,        -   (c) C₁₋₆alkyl, which is unsubstituted or substituted with            halogen, hydroxyl or phenyl or napthyl, and        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            halogen, hydroxyl or phenyl;    -   (2) —C₃₋₆cycloalkyl, where the cycloalkyl is unsubstituted or        substituted with one or more substituents selected from        —C₁₋₆alkyl and phenyl, where the alkyl and phenyl are        independently unsubstituted or substituted with one or more        substituents selected from the group consisting of:        -   (a) halogen,        -   (b) hydroxyl,        -   (c) C₁₋₆alkyl, which is unsubstituted or substituted with            halogen, hydroxyl or phenyl or napthyl, and        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            halogen, hydroxyl or phenyl;    -   (3) -phenyl, which is unsubstituted or substituted with one or        more substituents selected from the group consisting of:        -   (a) halogen,        -   (b) hydroxyl,        -   (c) C₁₋₆alkyl, which is unsubstituted or substituted with            halogen, hydroxyl or phenyl or napthyl, and        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds wherein R³ isselected from the group consisting of: cyclohexyl, cyclopentyl,sec-butyl, neo-pentyl and phenyl. An embodiment of the present inventionincludes compounds wherein R³ is cyclohexyl.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizingneuropeptide S receptor activity in a patient such as a mammal in needof such inhibition comprising the administration of an effective amountof the compound. The present invention is directed to the use of thecompounds disclosed herein as antagonists of neuropeptide S receptoractivity. In addition to primates, especially humans, a variety of othermammals can be treated according to the method of the present invention.The present invention is directed to a compound of the present inventionor a pharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for antagonizing neuropeptide S receptoractivity or treating the disorders and diseases noted herein in humansand animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asNeuropeptide S receptor agonists and/or antagonists may be readilydetermined without undue experimentation by methodology well known inthe art, including the “FLIPR Ca²⁺Flux Assay” (Hodder et al., J BiomolScreen, 9(5):417-26, 2004). In a typical experiment the Neuropeptide Sreceptor agonistic and antagonistic activity of the compounds of thepresent invention were determined in accordance with the followingexperimental method. For intracellular calcium measurements, Chinesehamster ovary (CHO) cells expressing the human Neuropeptide S receptor Agene (NPSr A) (T. Laitinen et al., Science 304:300, 2004), are grown inDulbecco's Modification of Eagle's Medium (DMEM) containing 4 mML-glutamine, 0.5 g/ml G418, 100 uM non-essential amino acids (glycine,L-alanine, L-asparagine, L-aspartic acid, L-glutamic acid, L-proline,and L-serine), 1 mM sodium pyruvate, 25 mM Hepes, pH 7.4, 100 U/mlpenicillin, 100 ug/ml streptomycin and 10% fetal bovine serum (FBS). Thecells are seeded at 15,000 cells/well into black 384-well clear bottomsterile plates coated with poly-D-lysine (BectonDickinson Labware). DMEMis from MediaTech Inc., FBS is from Hyclone Inc., and the remainingreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated for 24 hours at 37° C. and 5% CO₂. Human Neuropeptide S (Y-L.Xu et al., Neuron 43:487, 2004) as the agonist is prepared as a 400 nMstock solution in assay buffer pH 7.4 (HBSS containing 20 mM Hepes, 250uM probenecid, 0.1% (w/v) bovine serum albumin fraction V (BSA) and 800uM TR40 (Zhang et al., J Biomol Screening 8:571-77, 2003)). Testcompounds for the first addition are prepared as 10 mM stock solutionsin DMSO, then are serially tirated in DMSO, diluted into assay bufferand transferred into 384-well plates, giving 5× compound concentrationsfrom 50 uM in assay buffer plus 0.1% BSA, 800 uM TR40, and 2.5% DMSO.Human Neuropeptide S is used as a positive control at a 5× concentrationof 100 nM. After 24 hours of growth, cells are washed 3 times with 100ul wash buffer (assay buffer without TR40 or BSA), leaving 30 ul eachtime. Then 10 ul of 4× dye loading buffer is added, resulting in a 40 ulvolume of assay buffer plus 2.5 uM Fluo-4 AM ester, 0.02% pluronic acid,0.1% BSA and 800 uM TR40. Cells are incubated in dye loading buffer for60 min (37° C., 5% CO₂). After 60 minutes, plates are transferred to theFluorescent Imaging Plate Reader (FLIPR, Molecular Devices), where 10 ulof the 5× compound plate are added to the 40 ul existing volume.Fluorescence is measured for each well at 1 second intervals for 1minute then 6 second intervals for 3 minutes; and each fluorescence peakmaximum is compared to the fluorescence peak maximum induced by 20 nM(EC₁₀₀) human Neuropeptide S. For each tested compound, an EC₅₀ value(the effective concentration of compound needed to produce 50% of theNPS control response) is determined. After the initial 4 minute FLIPRread, 16.67 ul of 4×NPS agonist is immediately added to the 50 ulexisting well volume, giving a final concentration of NPS at its EC₈₀ of3 nM. Fluorescence is measured for each well at 1 second intervals for 1minute then 6 second intervals for 3 minutes; and each fluorescence peakmaximum is compared to the fluorescence peak maximum induced by 3 nM NPSwith 0.5% DMSO in assay buffer in place of test compound. For eachtested antagonist, IC₅₀ value (the concentration of compound needed toinhibit 50% of the agonist response) is determined. The intrinsicNeuropeptide S receptor agonist and antagonist activity of a compoundwhich may be used in the present invention may be determined by theseassays.

One skilled in the art can appreciate that the potentiator activity oftest compounds can also be determined by similar experimental methods byadding Neuropeptide S at its EC₂₀ concentration of 0.05 nM in the secondaddition, and determining if compounds sensitized the cells to NPS bymeasuring any increase in the FLIPR response.

In particular, the compounds of the following examples had activity inagonizing and/or antagonizing the human Neuropeptide S receptor in theaforementioned assays, generally with an IC₅₀ of less than about 10 uM.Many of compounds within the present invention had activity in agonizingand/or antagonizing the human Neuropeptide S receptor in theaforementioned assays with an IC₅₀ of less than about 100 nM. Additionaldata is provided herein. Such a result is indicative of the intrinsicactivity of the compounds in use as agonists and/or antagonists of humanNeuropeptide S receptor. The present invention also includes compoundswithin the generic scope of the invention which possess activity asagonists of the Neuropeptide S receptor

The Neuropeptide S receptor has been implicated in a wide range ofbiological functions. This has suggested a potential role for thesereceptors in a variety of disease processes in humans or other species.The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of a varietyof neurological and psychiatric disorders associated with neuropeptide Sreceptors, including one or more of the following conditions ordiseases: sleep disorders, sleep disturbances, including enhancing sleepquality, improving sleep quality, increasing sleep efficiency,augmenting sleep maintenance; increasing the value which is calculatedfrom the time that a subject sleeps divided by the time that a subjectis attempting to sleep; improving sleep initiation; decreasing sleeplatency or onset (the time it takes to fall asleep); decreasingdifficulties in falling asleep; increasing sleep continuity; decreasingthe number of awakenings during sleep; decreasing intermittent wakingsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; decreasing nocturnalarousals, especially early morning awakenings; increasing daytimealertness; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersincluding overeating and bulimia nervosa, hypertension, diabetes,elevated plasma insulin concentrations and insulin resistance,dyslipidemias, hyperlipidemia, endometrial, breast, prostate and coloncancer, osteoarthritis, obstructive sleep apnea, cholelithiasis,gallstones, heart disease, abnormal heart rhythms and arrythmias,myocardial infarction, congestive heart failure, coronary heart disease,sudden death, stroke, polycystic ovary disease, craniopharyngioma, thePrader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects,normal variant short stature, Turner's syndrome, and other pathologicalconditions showing reduced metabolic activity or a decrease in restingenergy expenditure as a percentage of total fat-free mass, e.g, childrenwith acute lymphoblastic leukemia, metabolic syndrome, also known assyndrome X, insulin resistance syndrome, reproductive hormoneabnormalities, sexual and reproductive dysfunction, such as impairedfertility, infertility, hypogonadism in males and hirsutism in females,fetal defects associated with maternal obesity, gastrointestinalmotility disorders, intestinal motility dyskinesias, obesity-relatedgastro-esophageal reflux, hypothalmic diseases, hypophysis diseases,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), breathlessness, cardiovascular disorders,inflammation, such as systemic inflammation of the vasculature,arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain,gallbladder disease, gout, kidney cancer, increased anesthetic risk,reducing the risk of secondary outcomes of obesity, such as reducing therisk of left ventricular hypertrophy; diseases or disorders whereabnormal oscillatory activity occurs in the brain, including depression,migraine, neuropathic pain, Parkinson's disease, psychosis andschizophrenia, as well as diseases or disorders where there is abnormalcoupling of activity, particularly through the thalamus; enhancingcognitive function, including cognitive dysfunctions that comprisedeficits in all types of attention, learning and memory functionsoccurring transiently or chronically in the normal, healthy, young,adult or aging population, and also occurring transiently or chronicallyin psychiatric, neurologic, cardiovascular and immune disorders;enhancing memory; increasing memory retention; increasing immuneresponse; increasing immune function; hot flashes; night sweats;extending life span; schizophrenia; muscle-related disorders that arecontrolled by the excitation/relaxation rhythms imposed by the neuralsystem such as cardiac rhythm and other disorders of the cardiovascularsystem; conditions related to proliferation of cells such asvasodilation or vasorestriction and blood pressure; cancer; cardiacarrhythmia; hypertension; congestive heart failure; conditions of thegenital/urinary system; disorders of sexual function and fertility;adequacy of renal function; responsivity to anesthetics; mood disorders,such as depression or more particularly depressive disorders, forexample, single episodic or recurrent major depressive disorders anddysthymic disorders, or bipolar disorders, for example, bipolar Idisorder, bipolar II disorder and cyclothymic disorder, mood disordersdue to a general medical condition, and substance-induced mooddisorders; anxiety disorders including acute stress disorder,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic attack, panic disorder, post-traumatic stress disorder,separation anxiety disorder, social phobia, specific phobia,substance-induced anxiety disorder and anxiety due to a general medicalcondition; acute neurological and psychiatric disorders such as cerebraldeficits subsequent to cardiac bypass surgery and grafting, stroke,ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma,perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage;Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis;ocular damage; retinopathy; cognitive disorders; idiopathic anddrug-induced Parkinson's disease; muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, seizure disorders, absence seizures, complex partial andgeneralized seizures; Lennox-Gastaut syndrome; cognitive disordersincluding dementia (associated with Alzheimer's disease, ischemia,trauma, vascular problems or stroke, HIV disease, Parkinson's disease,Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease,perinatal hypoxia, other general medical conditions or substance abuse);delirium, amnestic disorders or age related cognitive decline;schizophrenia or psychosis including schizophrenia (paranoid,disorganized, catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced psychotic disorder; dissociativedisorders including multiple personality syndromes and psychogenicamnesias; substance-related disorders, substance use, substance abuse,substance seeking, substance reinstatement, all types of psychologicaland physical addictions and addictive behaviors, reward-relatedbehaviors (including substance-induced delirium, persisting dementia,persisting amnestic disorder, psychotic disorder or anxiety disorder;tolerance, addictive feeding, dependence, withdrawal or relapse fromsubstances including alcohol, amphetamines, cannabis, cocaine,hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine,sedatives, hypnotics or anxiolytics); movement disorders, includingakinesias and akinetic-rigid syndromes (including Parkinson's disease,drug-induced parkinsonism, postencephalitic parkinsonism, progressivesupranuclear palsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),chronic fatigue syndrome, fatigue, including Parkinson's fatigue,multiple sclerosis fatigue, fatigue caused by a sleep disorder or acircadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); attentiondeficit/hyperactivity disorder (ADHD); conduct disorder; migraine(including migraine headache); headache; hyperalgesia; pain; enhanced orexaggerated sensitivity to pain such as hyperalgesia, causalgia, andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndrome I and II; arthriticpain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); conditions associated with visceral painsuch as irritable bowel syndrome, and angina; eating disorders; urinaryincontinence; substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis;schizophrenia; anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder); mood disorders (includingdepression, mania, bipolar disorders); trigeminal neuralgia; hearingloss; tinnitus; neuronal damage including ocular damage; retinopathy;macular degeneration of the eye; emesis; brain edema; pain, includingacute and chronic pain states, severe pain, intractable pain,inflammatory pain, neuropathic pain, post-traumatic pain, bone and jointpain (osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia), perioperative pain(general surgery, gynecological), chronic pain, neuropathic pain,post-traumatic pain, trigeminal neuralgia, migraine and migraineheadache.

Thus, in specific embodiments the present invention provides methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism ofneuropeptide S receptors. The dosage range will generally be about 0.5mg to 1.0 g. per patient per day which may be administered in single ormultiple doses. In one embodiment, the dosage range will be about 0.5 mgto 500 mg per patient per day; in another embodiment about 0.5 mg to 200mg per patient per day; and in yet another embodiment about 5 mg to 50mg per patient per day. Pharmaceutical compositions of the presentinvention may be provided in a solid dosage formulation such ascomprising about 0.5 mg to 500 mg active ingredient, or comprising about1 mg to 250 mg active ingredient. The pharmaceutical composition may beprovided in a solid dosage formulation comprising about 1 mg, 5 mg, 10mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg activeingredient. For oral administration, the compositions may be provided inthe form of tablets containing 1.0 to 1000 milligrams of the activeingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250,300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, such as once or twice per day. The compounds may beadministered before bedtime. For example, the compounds may beadministered about 1 Hour prior to bedtime, about 30 minutes prior tobedtime or immediately before bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other neuropeptide Santagonists, orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: insulin sensitizers including (i) PPARγantagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activator receptor α agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fabric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB 1 receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosedescribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,aminone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide, (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H₃ antagonists; AMPAagonists; PDE IV inhibitors; GABA_(A) inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl(benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexyl, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other neuropeptide S receptor antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neurotrophic factors, humanagouti-related protein antagonists, ghrelin receptor antagonists,histamine 3 receptor antagonists or inverse agonists, and neuromedin Ureceptor agonists, and pharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as a minorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following abbreviations are used herein: Me: methyl; Et:ethyl; i-Pr: isopropyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn:benzyl; Ac: acetyl; THF: tetrahydrofuran; DEAD: diethylazodicarboxylate;DIPEA: N,N-diisopropylethylamine; NMM: N-methylmorpholine; DMAP:4-dimthylaminopyridine; DMSO: dimethylsulfoxide; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; HOBT:hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; TEA:triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovineserum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide;MTBE: methyl tert-butyl ether; SOCl₂: thionyl chloride; CDI: carbonyldiimidazole; PyClu: 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidiniumhexafluorophosphate; dba: dibenzylideneacetone; S-Phos:2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; dppf:1,1′-bis-(diphenylphosphino)ferrocene; rt: room temperature; HPLC: highperformance liquid chromatography. The compounds of the presentinvention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

EXAMPLE 1

4,5-Dihydrooxepin-3(2H)-one

To a solution of 2,3,4,5-tetrahydrooxepin-3-ol (308 mg, 2.70 mmole, J.Org. Chem. 2001, 66, 3201-3205) in CH₂Cl₂ (10 ml) was added 500 mg 5 Asieves, NMO (379 mg, 3.24 mmole), then TPAP (47.4 mg, 0.135 mmole) atRT. After 72 hr the mixture was filtered through a pad of silica gelwashing with dichloromethane and concentrated to a light yellow oil (220mg, 73%). Used in the next step without purification.

Ethyl 4-(3-cyano-2,3,4,5-tetrahydrooxepin-3-yl)piperazine-1-carboxylate

4,5-Dihydrooxepin-3(2H)-one (220 mg, 1.962 mmole) and zinc iodide (31mg, 0.097 mmole) were combined neat. To this was added TMSCN (0.28 ml,2.089 mmole) slowly (cooling with cold water bath). After 1 hr asolution of 1-ethoxycarbonylpiperazine (0.32 ml, 2.195 mmole) in MeOH(10 ml) was added then the mixture was heated to reflux. After 16 hr themixture was cooled to RT and concentrated. Flash column chromatography(25% EtOAc/hexanes) gave the title compound as a clear oil (320 mg,58%). ¹H-NMR (CDCl₃, 500 MHz) 6.32 (d, J=6.34 Hz, 1 H), 4.80 (m, 1 H),4.31 (d, J=12.94 Hz, 1 H), 4.15 (m, 3 H), 3.55 (bs, 4 H), 2.64 (bs, 4H), 2.30 (bs, 3 H), 2.16 (m, 1 H), 1.27 (t, J=7.08 Hz, 3 H).

1-[3-(4-Methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methanamine

To a solution of ethyl4-(3-cyano-2,3,4,5-tetrahydrooxepin-3-yl)piperazine-1-carboxylate (320mg, 1.146 mmole) in dry THF (5 ml) was added LAH (1.75 ml, 3.50 mmole)at 0° C. After 30 min the mixture was warmed to RT. After 16 hr themixture was cooled to 0° C. and slowly quenched with 2M NaOH until gasevolution had ceased and a fine white precipitate formed. AnhydrousNa₂SO₄ was added and the mixture stirred for 15 min. The slurry wasfiltered through a pad of Celite washing with THF. The filtrate wasconcentrated to give the title compound as a clear oil (250 mg, 97%)which was used in the next step without purification. ¹H-NMR (CDCl₃, 500MHz) d 6.23 (d, J=6.83 Hz, 1 H), 4.60 (m, 1 H), 4.11 (dd AB, J=12.46 and58.83 Hz, 2 H), 2.77 (s, 2 H), 2.70 (m, 4 H), 2.43 (m, 4 H), 2.27 (s, 3H), 2.13 (m, 4 H).

1-Methyl-3-[({[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methyl}amino)methyl]quinolin-2(1H)-one

To a solution of1-[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methanamine(250 mg, 1.109 mmole) in 1,2-dichloroethane (4 ml) was added AcOH (290μL, 5.07 mmole) then 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde(190 mg, 1.015 mmole). After 20 min sodium triacetoxyborohydride (323mg, 1.522 mmole) was added. After 16 hr the mixture was diluted with 1Maqueous NaOH and extracted with CH₂Cl₂ (3×). The combined organic layerswere dried (MgSO₄), filtered, and concentrated. Flash columnchromatography (gradient, 0-10% MeOH/CH₂Cl₂) gave the title compound asa pale yellow oil (279 mg, 69%). ¹H-NMR (CDCl₃, 500 MHz) d 7.70 (s, 1H), 7.56 (m, 2 H), 7.35 (d, J=8.30 Hz, 1 H), 7.25 (m, 1 H), 6.24 (d,J=6.6 Hz, 1 H), 4.59 (m, 1 H), 4.25 (dd AB, J=12.94 and 44.19 Hz, 2 H),3.80 (m, 2 H), 3.74 (s, 3 H), 2.71-2.61 (m, 6 H), 2.44 (m, 4 H), 2.28(s, 3 H), 2.21-2.06 (m, 4 H), 1.51 (m, 1 H).

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methyl}cyclohexanecarboxamide

To a solution of1-methyl-3-[({[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methyl}amino)methyl]quinolin-2(1H)-one(100 mg, 0.252 mmole) in CH₂Cl₂ (1.5 ml) was added TEA (0.053 ml, 0.378mmole) then cyclohexanecarbonyl chloride (0.044 ml, 0.328 mmole). After2 hr the mixture was concentrated. The crude material was purified bypreparative reversed-phase HPLC (30×150 mm Waters Sunfire, 5-50%CH₃CN/water containing 0.1% TFA over 20 min at 50 mL/min). Fractionscontaining the product were pooled and concentrated. The residue wastaken up in MeOH then passed through Dowex 1×2-400 ion exchange resin(prewashed with 1M NaOH, H₂O, MeOH) washing with MeOH. The filtrate wasconcentrated to give the title compound as a white solid (89 mg, 70%).¹H-NMR (CDCl₃, 500 MHz) d 7.58 (t, J=8.30 Hz, 1 H), 7.52 (d, J=7.57 Hz,1 H), 7.39 (d, J=8.30 Hz, 1 H), 7.25 (m, 1 H), 7.22 (s, 1 H), 6.21 (d,J=6.34 Hz, 1 H), 5.24 (d, J=19.77 Hz, 1 H), 4.60 (m, 2 H), 4.44 (d,J=13.19 Hz, 1 H), 4.24 (d, J=14.16 Hz, 1 H), 4.05 (d, J=13.18 Hz, 1 H),3.78 (s, 3 H), 3.07 (d, J=14.16 Hz, 1 H), 2.74 (m, 1 H), 2.62 (m, 2 H),2.45-2.21 (m, 6 H), 2.26 (s, 3 H), 2.16-2.05 (m, 2 H), 1.82-1.48 (m, 9H), 1.25-1.06 (m, 3 H). HRMS (M+H)⁺ calculated 507.3330. found 507.3329.

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)oxepan-3-yl]methyl}cyclohexanecarboxamide

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methyl}cyclohexanecarboxamide(59 mg, 0.116 mmole) was hydrogenated at atmospheric pressure (H₂balloon) with 10% Pd/C (13 mg, 0.012 mmole) in EtOH at RT. After 16 hrthe mixture was filtered through a pad of Celite washing with EtOH andconcentrated to an off-white solid (57 mg, 96%). ¹H-NMR (CDCl₃, 500 MHz)d 7.58 (t, J=7.08 Hz, 1 H), 7.52 (d, J=6.59 Hz, 1 H), 7.39 (d, J=8.30Hz, 1 H), 7.25 (m, 1 H), 7.21 (s, 1 H), 5.34 (d, J=19.78 Hz, 1 H), 4.58(d, J=19.78 Hz, 1 H), 4.31 (d, J=14.41 Hz, 1 H), 4.01 (m, 1 H), 3.88 (ddAB, J=13.91 and 74.95 Hz, 1 H), 3.78 (s, 3 H), 3.37 (m, 1 H), 2.91 (d,J=14.65 Hz, 1 H), 2.80-2.26 (m, 12 H), 1.84-1.06 (m, 17 H). HRMS (M+H)⁺calculated 509.3486. found 509.3491.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite amine, acidchloride, and aldehyde starting materials were commercially available,described in the literature or readily synthesized by one skilled in theart of organic synthesis without undue experimentation.

Name MS m/z (M + H)N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[4- 495.3349(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]methyl}cyclohexanecarboxamideN-((4-[4-(1-methylethyl)piperazin-1-yl]tetrahydro-2H-pyran-4- 523.36857yl}methyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[4- 557.34958(4-phenylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]methyl}cyclohexanecarboxamideN-{[4-(4-benzylpiperazin-1-yl)tetrahydro-2H-pyran-4- 571.36666yl]methyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-({4-[4-(2-hydroxyethyl)piperazin-1-yl]tetrahydro-2H-pyran- 525.346164-yl}methyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(4- 481.317piperazin-1-yltetrahydro-2H-pyran-4- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-((4- 563.3187[4-(2,2,2-trifluoroethyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}methyl)cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 495.3324(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamideN-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3- 481.3167yl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide .4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 511.3288yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 566.3287(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-N~2~-(2,2,2-trifluoroethyl)-L-valinamideN-[3-methoxy-2-methyl-2-(4-methylpiperazin-1-yl)propyl]-N- 483.3334[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(3- 481.3174piperazin-1-yltetrahydro-2H-pyran-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 509.3487(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cycloheptanecarboxamide2-ethyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]- 483.3333N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}butanamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 511.3645(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-2-propylpentanamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 481.3172(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclopentanecarboxamide2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3 - 495.3327yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yljmethyl}acetamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 481.3169(4-methylpiperazin-1-yl)tetrahydrofuran-3-yl]methyl}cyclohexanecarboxamideN-{[3-(4-methyl-1,4-diazepan-1-yl)tetrahydro-2H-pyran-3 - 509.3492yl]methyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(2- 486.3114phenylpiperidin-1-yl)ethyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(2- 472.2959phenylpyrrolidin-1-yl)ethyl]cyclohexanecarboxamideN-{2-[benzyl(methyl)amino]ethyl}-N-[(1-methyl-2-oxo-1,2- 446.2802dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-5-phenyl-1,2-dihydropyridin-3-yl)methyl]- 521.3491N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide(1S,4R)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]- 507.3334N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}bicyclo[2.2.1]heptane-2-carboxamide3-methoxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 525.3446yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 563.3207(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-4-(trifluoromethyl)cyclohexanecarboxamide2-methyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 509.3497yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide .4-(1-methylethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 537.3807yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide .4-tert-butyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 551.397yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide2-cyclohexyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 509.3498yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}acetamide .4-methyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 483.3334yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}pentanamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 489.2872(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3- yl]methyl}benzamide3-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3 - 509.3499yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}propanamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3- 503.3026(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-2-phenylacetamide 2-cycloheptyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3 -523.3654 yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}acetamide3,3-difluoro-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 517.2988yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclopentanecarboxamide .4,4-difluoro-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 531.315yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamideN-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo- 528.261,2-dihydroquinolin-3-yl)methyl]-1-benzothiophene-2- carboxamideN-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo- 500.321,2-dihydroquinolin-3-yl)methyl]-3-phenylpropanamide(1R,2R,4R)-N-{[1-(4-methylpiperazin-1- 488.32yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide(1S,2S)-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N- 512.32[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-2-phenylcyclopropanecarboxamideN-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo- 436.281,2-dihydroquinolin-3-yl)methyl]cyclopropanecarboxamide3-methyl-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}- 452.32N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]butanamide3-cyclopentyl-1-{[1-(4-methylpiperazin-1- 479.33yl)cyclohexyl]methyl}-1-[(2-oxo-1,2-dihydroquinolin-3- yl)methyl]ureaN-[(1-morpholin-4-ylcyclohexyl)methyl]-N-[(2-oxo-1,2- 466.308dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-piperidin- 464.32851-ylcyclohexyl)methyl]cyclohexanecarboxamideN-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo- 479.3371,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1- 493.3522(4-methylpiperazin-1- yl)cyclohexyl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1- 465.3212(4-methylpiperazin-1- yl)cyclobutyl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1- 479.3367(4-methylpiperazin-1- yl)cyclopentyl]methyl}cyclohexanecarboxamide(1R,2R,4R)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 489.3218yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclopentyl]methyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 479.337yl)methyl]-N-{[1-(4-methylpiperazin-1- yl)cyclopentyl]methyl}acetamide2-(1-hydroxycyclopentyl)-N-[(1-methyl-2-oxo-1,2- 509.3487dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}acetamidecis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 509.3497yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin- 523.3663-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide cis-4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2- 523.364dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamidetrans-4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2- 523.3638dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3- 497.6yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamideN-{[1-(2-methoxyethyl)-2-oxo-1,2-dihydroquinolin-3- 537.6yl]methyl}-N-{[1-(4-methylpiperazin-1yl)cyclohexyl]methyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1- 494.54morpholin-4-ylcycloheptyl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1- 466.3048morpholin-4-ylcyclopentyl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1- 478.3428piperidin-1-ylcyclohexyl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1- 480.3217morpholin-4-ylcyclohexyl)methyl]cyclohexanecarboxamidecis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 494.54yl)methyl]-N-[(1-piperidin-1- ylcyclohexyl)methyl]cyclohexanecarboxamidecis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 496.51yl)methyl]-N-[(1-morpholin-4- ylcyclohexyl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1- 464.3269piperidin-1-ylcyclopentyl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1- 494.3373morpholin-4-ylcycloheptyl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1- 493.3533(4-methylpiperazin-1- yl)cyclohexyl]methyl}cyclohexanecarboxamide

The following compounds were prepared using the foregoing methodology,but substituting commercially supplied amines for1-[3-(4-Methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methanamine,as described in the foregoing Reaction Schemes and Examples. Therequisite starting materials were commercially available, described inthe literature or readily synthesized by one skilled in the art oforganic synthesis without undue experimentation.

MS m/z Name (M + H)N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2- 465.24piperidin-1-ylethyl)benzamide3-methyl-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 445.27phenyl-2-piperidin-1-ylethyl)butanamide3-tert-butyl-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-(2- 460.28phenyl-2-piperidin-1-ylethyl)urea2-methyl-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 422.2(1,2,3,4-tetrahydronaphthalen-1-yl)benzamideN-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-2-phenyl-N-(2- 479.26phenyl-2-piperidin-1-ylethyl)acetamideN-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1,2,3,4- 408.18tetrahydronaphthalen-1-yl)benzamideN-[1-(2-methylphenyl)piperidin-4-yl]-N-[(2-oxo-1,2- 457.27dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide3-methyl-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 388.22(1,2,3,4-tetrahydronaphthalen-1-yl)butanamideN-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2- 471.2piperidin-1-ylethyl)thiophene-2-carboxamide3-(2-chlorophenyl)-1-[(2-oxo-1,2-dihydroquinolin-3- 457.16yl)methyl]-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea3-(2-methoxyphenyl)-1-[(2-oxo-1,2-dihydroquinolin-3- 453.21yl)methyl]-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea3-cyclopentyl-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1- 472.28(2-phenyl-2-piperidin-1-ylethyl)urea3-cyclohexyl-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1- 486.3(2-phenyl-2-piperidin-1-ylethyl)urea2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 501.3203yl)methyl]-N-[2-(4-methylpiperazin-1-yl)-2- phenylethyl]acetamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2- 501.3204(4-methylpiperazin-1-yl)-2- phenylethyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 486.3108phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamide2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 425.2921yl)methyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]acetamide2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 486.3108yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)acetamidecis-4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2- 516.3221dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamide2-(1-hydroxycyclopentyl)-N-[(1-methyl-2-oxo-1,2- 524.2908dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)acetamidecis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 502.3064yl)methyl]-N-(2-phenyl-2-piperidin-1- ylethyl)cyclohexanecarboxamideN-(1-benzylpiperidin-3-yl)-N-[(1-methyl-2-oxo-1,2- 472.2934dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl]-N-[(1-methyl- 458.28022-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 528.3585{4-[2-(4-methylphenyl)ethyl]piperidin-1- yl}ethyl)cyclohexanecarboxamideN-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]- 518.3014N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]-N-[(1-methyl-2-oxo- 444.441,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[2-(4-benzylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2- 501.53dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[2-(4-benzylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2- 501.52dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 486.3111[3-(2-methylphenyl)pyrrolidin-1- yl]ethyl}cyclohexanecarboxamideN-{2-[2-(1H-indol-2-yl)piperidin-1-yl]ethyl}-N-[(1-methyl-2- 525.3222oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamide.1-tert-butyl 2-methyl (2S,4S)-4-{(cyclohexylcarbonyl)[(1- 526.2931methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}pyrrolidine-1,2-dicarboxylateN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2- 536.3021(2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)ethyl]cyclohexanecarboxamide benzyl3-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 592.3192dihydroquinolin-3-yl)methyl]amino}-2-phenylpiperidine-1- carboxylateN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 487.306piperidin-1-yl-2-pyridin-3-ylethyl)cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 518.3015[2-(phenoxymethyl)morpholin-4- yl]ethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2- 425.2909(4-methylpiperazin-1-yl)ethyl]cyclohexanecarboxamideN-[(3R)-1-(1-methylethyl)pyrrolidin-3-yl]-N-[(1-methyl-2- 410.2799oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[2-(dimethylamino)-1-methylethyl]-N-[(1-methyl-2-oxo- 384.2641,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide benzyl{2-[(tert-butoxycarbonyl)amino]ethyl}(2- 619.3487{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}ethyl)carbamateN-{2-[4-(2,3-dihydro-1H-inden-2-yl)piperazin-1-yl]ethyl}-N- 527.3382[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamidetert-butyl [(3R,4R)-1-benzyl-4-{(cyclohexylcarbonyl)[(1- 573.3432methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}pyrrolidin-3-yl]carbamateN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 515.3062[4-(phenylcarbonyl)piperazin-1- yl]ethyl}cyclohexanecarboxamideN-{2-[3-(1,3-benzoxazol-2-yl)piperidin-1-yl]ethyl}-N-[(1- 527.3034methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[2-(4-benzylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2- 501.3227dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 435.3001[(2S)-1,7,7-trimethylbicyclo[2.2.1]hept-2- yl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 443.2691[(1S,2R)-2-phenylcyclopentyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 472.2954[(3R,4R)-1-methyl-3-phenylpiperidin-4- yl]cyclohexanecarboxamideN-[2-(3,3-dimethylpiperidin-2-yl)ethyl]-N-[(1-methyl-2-oxo- 438.31151,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 443.269[(1S,2S)-2-phenylcyclopentyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 443.2696phenylcyclopentyl)cyclohexanecarboxamideN-[3-(diethylamino)-1,1-dimethylpropyl]-N-[(1-methyl-2- 440.3266oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N- 450.3111[(1S,9aR)-octahydro-2H-quinolizin-1- ylmethyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1- 424.2954methyl-3-pyrrolidin-1-ylpropyl)cyclohexanecarboxamideN-(1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo- 440.29031,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-(1,1-dimethyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2- 454.3058oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1,1-dimethyl-3-pyrrolidin-1-ylpropyl)-N-[(1-methyl-2- 438.311oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2- 472.2954(3-phenylpyrrolidin-1-yl)ethyl]cyclohexanecarboxamideN-[2-(dimethylamino)-2-pyridin-2-ylethyl]-N-[(1-methyl-2- 447.2752oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 507.3687[4-(1-pyrrolidin-1-ylethyl)piperidin-1- yl]ethyl}cyclohexanecarboxamidetert-butyl {[1-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 539.3584dihydroquinolin-3-yl)methyl]amino}ethyl)piperidin-3- yl]methyl}carbamatetert-butyl 1-({(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 544.3173dihydroquinolin-3-yl)methyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateN-[(3R)-1-(1-methylethyl)pyrrolidin-3-yl]-N-[(1-methyl-2- 410.2798oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{[1-(1-methylethyl)pyrrolidin-2-yl]methyl}-N-[(1-methyl- 424.29552-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{[1-(1-methylethyl)pyrrolidin-2-yl]methyl}-N-[(1-methyl- 424.29552-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(3S)-1-benzylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2- 458.43dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 511.53piperazin-1-ylethyl)cyclohexanecarboxamideN-[(3R)-1-benzylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2- 458.44dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-(1,1-dimethyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 452.49oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamide tert-butyl4-(3-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 553.52dihydroquinolin-3-yl)methyl]amino}-3-methylbutyl)piperazine-1-carboxylate tert-butyl4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 510.44dihydroquinolin-3-yl)methyl]amino}ethyl)piperidine-1- carboxylateN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 410.29piperidin-4-ylethyl)cyclohexanecarboxamide

EXAMPLE 2

To an oven dried flask at 0 C was added anhydrous CH₂Cl₂ (200 mL)followed by 4 (8.66 g, 39 mmol). After 5 minutes, a mixture of 1 (28.1g, 390 mmol) and 2 (57.4 g, 390 mmol) in 50 mL anhydrous CH₂Cl₂ wasadded to the reaction. Next a solution of allyltrimethylsilane 3 (44.5g, in 50 ml CH₂Cl₂) was added to the reaction. The solution was stirredand warmed to ambient temperature overnight. The reaction was quenchedwith NH₃ saturated CHCl₃ (20 mL) and concentrated in vacuo to give anoil. Flash chromatography (silica, 5-10% EtOAc/hexanes over 20 min)provided 5 (26 g, 39% yield) as a clear oil.

To 6 (9.2 g, 53.7 mmol) in ethylene glycol (270 ml) was added hydrazinehydrate (10.42 ml, 215 mmol) and potassium hydroxide (36.2 g, 645 mmol).The reaction was heated to reflux and stirred overnight. The reactionwas cooled to room temperature and then diluted with sat. NaHCO₃,extracted with CH₂Cl₂ 3 times. The organics were combined, dried overNa₂SO₄ and concentrated in vacuo to provide a clear oil. Flashchromatography (silica, 12 g column, 0-8% MeOH/NH₃ sat'd CHCl₃) provided7 (3.5 g, 57.5% yield) as a clear oil.

A mixture of 8 (900 mg, 4.81 mmol) and 9 (560 mg, 4.95 mmol) indichloroethane (24 mL) was stirred at room temperature for 45 minutes.Next sodium triacetoxyborohydride (3.06 g, 14.42 mmol) and acetic acid(1.65 ml, 28.8 mmol) were added. After 1 hour, the reaction wascomplete. The reaction was quenched with sat. NaHCO₃, extracted withCH₂Cl₂ 3 times. The organics were combined, dried over Na₂SO₄ andconcentrated in vacuo to yield a yellow oil. Flash chromatography(silica, 0-5% MeOH/NH₃ saturated CH₃Cl) provided 10 (350 mg, 25% yield)as a yellow solid.

To 10 (300 mg, 1.055 mmol) in dichloroethane (10 ml) was addedcyclohexane carbonyl chloride (1.4 ml, 10.55 mmol) anddiisopropylethylamine (2.7 ml, 15.82 mmol). The reaction was stirredovernight. Next the reaction was quenched with MeOH and diluted withCH₂Cl₂, washed with sat. NaHCO₃, dried over Na₂SO₄ and concentrated invacuo to give an orange oil. Flash chromatography (silica, 8 g col,2-35% EtOAc/hexanes) provided 11 (284 mg, 68% yield) as a yellow foam.

To a mixture of 11 (284 mg, 0.72 mmol) in t-BuOH (1.8 mL) and THF (0.6mL) at room temperature was added N-methylmorpholine N-oxide (337 mg,1.44 mmol) followed by osmium tetroxide (0.027 mL, 0.022 mmol). Themixture was stirred at room temperature overnight. The reaction was thendiluted with phosphate buffer (pH 7, 5 mL). Sodium periodate (693 mg,3.24 mmol) was then added and the cloudy solution was stirred vigorouslyfor 2 hours. Next it was diluted with water and extracted three timeswith ethyl acetate. The combined organics were dried over Na₂SO₄,filtered and concentrated in vacuo to give 12 as a yellow solid (251 mg,88%).

N-(1-ethyl-1-methyl-3-(4,4-difluoro-piperidin-1-yl)propyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide

To 12 (125 mg, 0.315 mmol) and 13 (54.6 mg, 0.347 mmol) indichloroethane (2 ml) was added sodium triacetoxyborohydride (100 mg,0.473 mmol), acetic acid (0.054 ml, 0.946 mmol) and sodium acetate (51.7mg, 0.63 mmol). The reaction was stirred at room temperature for onehour. Next the reaction was diluted with sat. NaHCO₃ and extracted withCH₂Cl₂ 3 times. The combined organics were dried over Na₂SO₄, filtered,and concentrated in vacuo to give an oil. Acidic reversed phasechromatography provided 14 as a foamy solid (66 mg, 41.7% yield). ¹H NMR(500 MHz, CD₃OD) 7.60 (t, 1H), 7.56 (d, 1H, J=8 Hz), 7.42 (d, 1H, J=8Hz), 7.29 (d, 1H, J=8 Hz), 4.50 (m, 2H), 3.79 (s, 3H), 3.49 (s, 3H),2.55 (m, 4H), 2.44 (m, 1H), 2.19 (m, 2H), 1.89 (m, 12H), 1.20 (s, 4H),0.87 (m, 3H). HRMS (ES, M+1) calc'd 502.3240. found 502.3239.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation.

MS m/z Name (M + H)N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 468.3231oxo-1,2-dihydroquinolin-3-yl)methyl]tetrahydro-2H-pyran-4- carboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-4,4-difluoro-N- 502.325[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2- 468.3228oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2- 468.3229oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 468.3221oxo-1,2-dihydroquinolin-3-yl)methyl]tetrahydro-2H-pyran-3- carboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 468.322oxo-1,2-dihydroquinolin-3-yl)methyl]tetrahydro-2H-pyran-2- carboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 468.3222oxo-1,2-dihydroquinolin-3-yl)methyl]-2-(tetrahydrofuran-3- yl)acetamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-2-(1- 482.3378hydroxycyclopentyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]acetamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 466.4oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 466.4oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 466.4oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2- 468.4oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2- 470.3oxo-1,2,5,6,7,8-hexahydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2- 472.3oxo-1,2,5,6,7,8-hexahydroquinolin-3- yl)methyl]cyclohexanecarboxamide

EXAMPLE 3

To a solution of potassium carbonate (1.59 g, 11.5 mmol) and sodiumiodide (37 mg, 0.247 mmol) in DMF (15 mL) with stirring was added 1(1.017 g, 3.88 mmol) and 2 (1.107 g, 4.36 mmol). The reaction was heatedto 50 C overnight. Next the reaction was cooled to room temperature,partitioned with EtOAc and H₂O, washed with H₂O and brine. The organicswere dried over Na₂SO₄ (anhydrous), decanted, concentrated and dried toyield clear oil. Flash chromatography [silica, 120 g column, 0-100%EtOAc/hexane] provided a white foam (810 mg, 47% yield).

To a solution of 4 (790 mg, 1.814 mmol) in EtOH (10 ml) was addedhydrazine monohydrate (200 uL, 3.25 mmol). The reaction was heated to 80C. After 5 hours, added additional hydrazine (100 uL, 1.6 mmol) andcontinued heating for 24 hours. The reaction was cooled and filtered.The filtrate was concentrated and dried to yield 5 (792 mg, 140% yield)an off-white foam.

A mixture of 6 (50 mg, 0.267 mmol) and 5 (82 mg, 0.267 mmol) indichloroethane (2 mL) was stirred at room temperature for 45 minutes.Next sodium triacetoxyborohydride (170 mg, 0.801 mmol) and acetic acid(0.092 ml, 1.6 mmol) were added. After 24 hours the reaction wascomplete. The reaction was quenched with sat. NaHCO₃, extracted withCH₂Cl₂ three times. The organics were combined, dried over Na₂SO₄ andconcentrated in vacuo to yield 7 as a yellow oil (127 mg, 100%.

To 7 (127 mg, 0.267 mmol) in dichloroethane (1 ml) was added cyclohexanecarbonyl chloride (0.054 ml, 0.401 mmol) and diisopropylethylamine(0.233 ml, 1.335 mmol). The reaction was stirred overnight. Next thereaction was quenched with MeOH and diluted with CH₂Cl₂, washed withsat. NaHCO₃, dried over Na₂SO4 and concentrated in vacuo to give an oil.Basic reversed phase chromatography provided 8 (60 mg, 68%) as a foam.

N-{2-[2-phenylpiperazin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide

To 8 (60 mg, 0.102 mmol) in CH₂Cl₂ (1 ml) was added TFA (0.6 ml, 7.5mmol). After 2 hours, the reaction was concentrated and azeotroped withtoluene to give a yellow oil. Acidic reverse phase chromatographyprovided 9 (27 mg, 54% yield) as a foam. ¹H NMR (500 MHz, CD₃OD) d 7.58(t, 1H, J=8 Hz), 7.52 (m, 1H), 7.49 (d, 1H, J=8 Hz), 7.39 (d, 1H, J=8Hz), 7.31 (m, 3H), 7.23 (m, 3H), 4.45 (m, 4H), 4.20 (d, 1H, J=15 Hz),3.75 (s, 3H), 3.55 (m, 2H), 3.44 (m, 1H), 3.37 (m, 1H), 3.22 (m, 3 H),3.00 (m, 4H), 2.71 (m, 3H), 2.35 (m, 1H), 2.25 (m, 2H), 2.15 (m, 2H),1.5 (m, 3H).

HRMS (ES, M+1) calc'd 487.2995. found 487.3062.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation.

Name MS m/z (M + H) N-{2-[4-(cyclopropylmethyl)-2-phenylpiperazin-1-541.3532 yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[4-(cyclopropylcarbonyl)-2-phenylpiperazin-1- 555.3338yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[4-(cyclobutylmethyl)-2-phenylpiperazin-1- 555.3687yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[2-(4-benzyl-2-phenylpiperazin-1-yl)ethyl]-N-[(1- 577.3527methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamide

EXAMPLE 4

(4-hydroxytetrahydro-2H-pyran-4-yl)(phenyl)acetonitrile

To benzyl cyanide (1.970 ml, 19.39 mmol) was added THF (100 ml) and thesolution cooled to −78° C. n-butyllithium (2.5 M in hexanes, 7.84 ml,19.59 mmol) was added dropwise over 20 min via syringe pump and thesolution stirred 30 min. Tetrahydro-4H-pyran-4-one (1.791 ml, 19.39mmol) was added over 20 min via syringe pump and the solution stirredfor 3 hours. The reaction was quenched by addition of ice-cold satd.NH₄Cl and then partitioned between cold satd. NH₄Cl and CH₂Cl₂. Theaqueous portion was extracted 2×CH₂Cl₂, dried (Na₂SO₄), and concentratedin vacuo. Took up material in CH₂Cl₂ and allowed to crystallize over theweekend. The crystals were washed with diethyl ether and used withoutfurther purification. 3.14 g, 81%.

phenyl(tetrahydro-4H-pyran-4-ylidene)acetonitrile

(4-hydroxytetrahydro-2H-pyran-4-yl)(phenyl)acetonitrile (500 mg, 2.301mmol) was dissolved in pyridine (10 ml). SOCl₂ (1.680 ml, 23.01 mmol)was added and the reaction was stirred for 25 minutes then concentratedin vacuo. The crude material was purified by silica gel chromatographyon an Isco Companion (5 to 35% EA/hexanes over 20 min, 40 g silicacolumn). The desired fractions were combined and concentrated in vacuo.450 mg, 98%.

2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethanaminium chloride

To phenyl(tetrahydro-4H-pyran-4-ylidene)acetonitrile (450 mg, 2.258mmol) in ethanol (11 ml) was added HCl (12.1 M, 1.867 ml, 22.58 mmol)then 10% Pd/C (48.1 mg, 0.045 mmol) as a slurry in ethanol. The reactionmixture was put under H₂ balloon pressure for 21 hours. The reaction wasfiltered through a 0.45 um syringe-tip filter, then concentrated invacuo. The product was used without further purification.

1-methyl-3-({[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)quinolin-2(1H)-one

1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (35 mg, 0.187 mmol),sodium acetate (19.94 mg, 0.243 mmol), and2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethanaminium chloride (45.2 mg,0.187 mmol) were combined in 1,2 dichloroethane (2 ml). Acetic acid(0.021 ml, 0.374 mmol) and sodium triacetoxyborohydride (119 mg, 0.561mmol) were added and the reaction stirred for 20 hours. The mixture waspartitioned between CH₂Cl₂ and satd. bicarb and the aqueous portion wasextracted 3×CH₂Cl₂. The organic portion was dried (Na₂SO₄) andconcentrated in vacuo. The resulting material was purified byreversed-phase chromatography (10-60% ACN in water (with 2 ml/l NH₄OH)over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18 column).Desired fractions were concentrated in vacuo. 50.5 mg, 73%.

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]cyclohexanecarboxamide

To1-methyl-3-({[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)quinolin-2(1H)-one(46.5 mg, 0.124 mmol) in CH₂Cl₂ (3 ml) and added DIEA (0.043 ml, 0.247mmol) then cyclohexanecarbonyl chloride (0.018 ml, 0.136 mmol). Thereaction was stirred for 1 hour and then concentrated in vacuo. Purifiedby reversed-phase chromatography (15-75% ACN in water (with 0.5 ml/lNH₄OH), 20×100 mm Phenomenex Gemini C18 column). Desired fractions wereconcentrated in vacuo. HRMS [M+H]1+ 487.2962. 400 MHz ¹H NMR (CDCl₃) δ7.59-7.47 (m, 2 H), 7.37 (d, J=8.52 Hz, 1 H), 7.33-7.13 (m, 7 H), 4.26(d, J=18.4, 1 H), 4.17-3.95 (m, 2 H), 3.88-3.76 (m, 2 H), 3.74 (s, 3 H),3.44-3.23 (m, 3 H), 2.97-2.91 (m, 0.8 H, rotational isomer A), 2.67-2.62(m, 0.2 H, rotational isomer B), 2.42-2.19 (m, 0.2 H, rotational isomerB), 2.15-2.08 (m, 0.8 H, rotational isomer A), 1.95-0.95 (m, 15 H). 29.4mg, 49%.

Analogous hydroxyl-substituted compounds were obtained by omitting theSOCl₂-mediated elimination step:

2-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-phenylethanaminium chloride

To (4-hydroxytetrahydro-2H-pyran-4-yl)(phenyl)acetonitrile (50 mg, 0.230mmol) in ethanol (2 ml) was added HCl (0.190 ml, 2.301 mmol) then 10%Pd/C (49.0 mg, 0.046 mmol) as a slurry in ethanol. The reaction mixturewas put under H₂ balloon pressure for 15 hours. The reaction wasfiltered through a 0.45 um syringe-tip filter, then concentrated invacuo. The product was used without further purification. 49.6 mg, 84%.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation.

Name MS m/z (M + H) N-[2-(4-hydroxytetrahydro-2H-pyran-4-yl)-2- 503.2927phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]- 487.2962N-[2-phenyl-2-(tetrahydro-2H-pyran-4- yl)ethyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]- 487.2989N-[2-phenyl-2-(tetrahydro-2H-pyran-3- yl)ethyl]cyclohexanecarboxamide

EXAMPLE 4

tert-butyl 4-[cyano(phenyl)methyl]-4-hydroxypiperidine-1-carboxylate

Benzyl cyanide (2.96 ml, 25.6 mmol) in THF (125 ml) was cooled to −78°C. nBuLi (16.17 ml, 25.9 mmol) was added dropwise over 20 min viasyringe pump, and the reaction stirred for 30 min. 1-BOC-4-piperidone(5.10 g, 25.6 mmol) in THF (20 ml) was added over 20 min via syringepump and the reaction stirred for 2.5 hours. While still cold, thereaction was quenched with satd. NH₄Cl and allowed to warm overnight.The mixture was partitioned between CH₂Cl₂ and satd. NH₄Cl, the aqueousportion extracted 3×CH₂Cl₂, and the organic portion dried (Na₂SO₄) thenconcentrated in vacuo. The resulting material was carried on withoutfurther purification.

tert-butyl 4-[cyano(phenyl)methylene]piperidine-1-carboxylate

To tert-butyl 4-[cyano(phenyl)methyl]-4-hydroxypiperidine-1-carboxylate(1.8 g, 5.69 mmol) in pyridine (4 ml) was added SOCl₂ (2.076 ml, 28.4mmol) and the reaction was stirred for 10 min. The reaction mixture wasconcentrated in vacuo. The resulting crystalline solid was adsorbed ontosilica gel and purified by silica gel chromatography in an IscoCompanion. The desired fractions were combined and concentrated invacuo. 1.18 g, 70% over two steps.

tert-butyl 4-(2-amino-1-phenylethyl)piperidine-1-carboxylate

tert-butyl 4-[cyano(phenyl)methylene]piperidine-1-carboxylate (1.18 g,3.95 mmol) in ethanol (15 ml) was saturated with NH₃ at ambienttemperature and Raney nickel (1 ml, 3.95 mmol) in water was added. Thereaction was placed on a Parr reactor under H₂ pressure (48 psi) for 19hours. The reaction mixture was then re-saturated with NH₃ andadditional Raney nickel (1 ml, 3.95 mmol) was added before placing backon the Parr reactor for an additional 5.5 hours. The reaction mixturewas filtered through Celite, washing with EtOH, and concentrated invacuo. The product was carried on without further purification.

tert-butyl4-(2-{[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate

1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (0.590 g, 3.15 mmol),tert-butyl 4-(2-amino-1-phenylethyl)piperidine-1-carboxylate (1.2 gcrude, 3.94 mmol), and acetic acid (0.677 ml, 11.83 mmol) were combinedin CH₂Cl₂ (20 ml). Sodium triacetoxyborohydride (2.506 g, 11.83 mmol)was added and the reaction stirred for 16 hours. The mixture waspartitioned between CH₂Cl₂ and satd. bicarb, the aqueous portionextracted 3×CH₂Cl₂, and the organic portion dried (Na₂SO₄) thenconcentrated in vacuo. The product was carried on without furtherpurification.

tert-butyl4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate

tert-butyl4-(2-{[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate(1.61 g crude, 3.39 mmol), EDC (1.298 g, 6.77 mmol), HOAT (0.461 g, 3.39mmol), DIEA (1.182 ml, 6.77 mmol), and cyclohexanecarboxylic acid (0.504ml, 4.06 mmol) were combined in CH₂Cl₂ and the reaction stirred for 15hours. The mixture was partitioned between CH₂Cl₂ and satd. bicarb, theaqueous portion extracted 3×CH₂Cl₂, and the organic portion dried(Na₂SO₄) then concentrated in vacuo. The resulting material was purifiedby silica gel chromatography on an Isco Companion. The desired fractionswere combined and concentrated in vacuo. 1.63 g, 82% over two steps.

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-4-ylethyl)cyclohexanecarboxamide

tert-butyl 4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate(1.63 g, 2.78 mmol) in CH₂Cl₂ (5 ml) was added to 4 M HCl in dioxane (20mL, 80 mmol) at 0° C. and the reaction stirred for 1.5 hours beforebeing poured into satd. bicarb. The mixture was partitioned betweenCH₂Cl₂ and satd. bicarb, the aqueous portion extracted 3×CH₂Cl₂, and theorganic portion dried (Na₂SO₄) then concentrated in vacuo. 1.35 g, 100%.

4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)-1-(2,2-dimethylpropyl)piperidiniumtrifluoroacetate

Reaction was run in a library format; only the amine starting materialwas accurately measured. MP-cyanoborohydride (0.165 mmol) andtrimethylacetaldehyde (˜21.3 mg, 0.247 mmol) were combined.N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-4-ylethyl)cyclohexanecarboxamide(40 mg, 0.082 mmol) in CH₂Cl₂ (2 mL) and AcOH (0.014 ml, 0.247 mmol)were then added. The reaction vial was sealed and put on a rotator for15 hours, after which time the mixture was filtered and concentrated.The resulting material was taken up in DMSO and sent to a purificationgroup for reversed-phase purification, sample concentration, analysis,dilution, and plating. HRMS [M+H]1+ 556.3899. ¹H NMR (400 MHz, CDCl₃): δ7.76-7.73 (m, 1 H), 7.64-7.60 (m, 1 H), 7.55 (d, J=8.42, 1 H), 7.46 (s,1 H), 7.37-7.18 (m, 6 H), 4.22-4.14 (m, 1 H), 3.83-3.77 (m, 1 H),3.69-3.61 (m, 4 H), 3.04-2.89 (m, 5 H), 2.55 (s, 3 H), 2.41-2.28 (m, 1H), 2.10-1.92 (m, 2 H), 1.82-1.73 (m, 1 H), 1.61-1.52 (m, 4 H),1.45-1.38 (m, 1 H), 1.32-1.25 (m, 3 H), 1.20-1.05 (m, 4 H), 1.00 (s, 9H). 5 mg, 11%.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples, in particular by omittingthe SOCl2-mediated elimination step. The requisite starting materialswere commercially available, described in the literature or readilysynthesized by one skilled in the art of organic synthesis without undueexperimentation.

MS m/z Name (M + H)N-[2-(4-hydroxy-1-methylpiperidin-4-yl)-2-phenylethyl]-N- 516.319[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamidetert-butyl 4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 602.3607dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)-4-hydroxypiperidine-1-carboxylateN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2- 484.3001phenyl-2-piperidin-4-ylethyl)cyclohexanecarboxamideN-[2-(4-hydroxypiperidin-4-yl)-2-phenylethyl]-N-[(1- 502.31methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-2-phenylethyl}-N- 530.3364[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{2-[4-hydroxy-1-(2-hydroxyethyl)piperidin-4-yl]-2- 546.336phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 567.3365[1-(1,3-oxazol-5-ylmethyl)piperidin-4-yl]-2-phenylethyl}cyclohexanecarboxamideN-{2-[1-(2,3-dihydroxypropyl)piperidin-4-yl]-2- 560.3512phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide[4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2- 544.3184dihydroquinolin-3-yl)methyl]amino}-1- phenylethyl)piperidin-1-yl]aceticacid N-{2-[1-(cyclopropylmethyl)piperidin-4-yl]-2-phenylethyl}- 540.3602N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[1-(2,2-dimethylpropyl)piperidin-4-yl]-2- 556.3899phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[1-(cyclopentylmethyl)piperidin-4-yl]-2-phenylethyl}- 568.3917N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 542.3753[1-(2-methylpropyl)piperidin-4-yl]-2- phenylethyl}cyclohexanecarboxamideN-[2-(1-butylpiperidin-4-yl)-2-phenylethyl]-N-[(1-methyl-2- 542.3754oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{2-[1-(3-methylbutyl)piperidin-4-yl]-2-phenylethyl}-N- 556.391[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{2-[1-(1H-imidazol-2-ylmethyl)piperidin-4-yl]-2- 566.3518phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 567.3359[1-(1,3-oxazol-2-ylmethyl)piperidin-4-yl]-2-phenylethyl}cyclohexanecarboxamideN-[2-(1-benzylpiperidin-4-yl)-2-phenylethyl]-N-[(1-methyl- 576.3622-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 577.3563phenyl-2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 577.3573phenyl-2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 577.3573phenyl-2-[1-(pyridin-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-(2-{1-[(1-methyl-1H-imidazol-2-yl)methyl]piperidin-4- 580.3684yl}-2-phenylethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 583.3136phenyl-2-[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 567.3369[1-(1,3-oxazol-4-ylmethyl)piperidin-4-yl]-2-phenylethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 566.3538phenyl-2-[1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 566.352phenyl-2-[1-(1H-pyrazol-5-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 567.3477phenyl-2-[1-(1H-1,2,3-triazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamideN-{2-[1-(cyclopropylmethyl)piperidin-4-yl]ethyl}-N-[(1- 464.3271methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2- 490.3177[1-(1H-pyrazol-4-ylmethyl)piperidin-4- yl]ethyl}cyclohexanecarboxamideN-{2-[1-(1H-imidazol-2-ylmethyl)piperidin-4-yl]ethyl}-N- 490.3176[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{2-[1-(2,2-dimethylpropyl)piperidin-4-yl]ethyl}-N-[(1- 480.3584methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-{2-[1-(cyclopropylmethyl)piperidin-4-yl]-2-phenylethyl}- 540.3577N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[1-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl]-2- 556.3528phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[4-hydroxy-1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]- 582.34462-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[4-hydroxy-1-(1H-imidazol-2-ylmethyl)piperidin-4- 582.3445yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-{2-[1-(2,2-dimethylpropyl)-4-hydroxypiperidin-4-yl]-2- 572.3844phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide

EXAMPLE 5

3-{[(1-benzyl-3-methylpyrrolidin-3-yl)amino]methyl}-1-methylquinolin-2(1H)-one

1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (956 mg, 5.11 mmol),1-benzyl-3-methylpyrrolidin-3-amine (972 mg, 5.11 mmol), and acetic acid(0.877 ml, 15.32 mmol) were combined in CH₂Cl₂ (25 ml) and stirred for30 min. Sodium triacetoxyborohydride (3248 mg, 15.32 mmol) was added andthe reaction stirred for 2.5 hours before being partitioned betweenCH₂Cl₂ and satd. bicarb. The aqueous portion was extracted 3×CH₂Cl₂, andthe organic portion dried (Na₂SO₄) then concentrated in vacuo. Theresulting material was carried on crude.

N-(1-benzyl-3-methylpyrrolidin-3-yl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide

To3-{[(1-benzyl-3-methylpyrrolidin-3-yl)amino]methyl}-1-methylquinolin-2(1H)-one(1846 mg, 5.11 mmol) in CH₂Cl₂ (25 ml) was added DIEA (1.338 ml, 7.66mmol). Cyclohexane carbonyl chloride (0.757 ml, 5.62 mmol) was added andthe reaction stirred for 2 hours. The reaction was quenched with MeOHthen concentrated in vacuo. The resulting material was twice purified bysilica gel chromatography on an Isco Companion (5-35% acetone/hexane forfirst run, 5-25% acetone/hexane for second run). 2.12 g, 88% over twosteps.

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(3-methylpyrrolidin-3-yl)cyclohexanecarboxamide

N-(1-benzyl-3-methylpyrrolidin-3-yl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide(1750 mg, 3.71 mmol) and ammonium formate (936 mg, 14.84 mmol) werecombined in MeOH (37 mL). 10% Pd/C (350 mg, 3.288 mmol) was added as aslurry in MeOH and the reaction heated to 60° C. for 15 hours. Thereaction mixture was filtered through a 0.45 um syringe-tip filter andconcentrated in vacuo. The resulting material was partitioned betweenCH₂Cl₂ and satd. bicarb, the aqueous portion extracted 3×CH₂Cl₂, and theorganic portion dried (Na₂SO₄) then concentrated in vacuo. This materialwas carried on without further purification. 1.5 g, 106%.

N-[1-(cyclobutylmethyl)-3-methylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide

N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(3-methylpyrrolidin-3-yl)cyclohexanecarboxamide(300 mg, 0.786 mmol), cyclobutanecarbaldehyde (99 mg, 1.180 mmol), andacetic acid (0.090 ml, 1.573 mmol) were combined in CH₂Cl₂ (70 ml).Sodium triacetoxyborohydride (333 mg, 1.573 mmol) was added and thereaction stirred for 2.5 hours. The reaction mixture was partitionedbetween CH₂Cl₂ and satd. bicarb, the aqueous portion extracted 3×CH₂Cl₂,and the organic portion dried (Na₂SO₄) then concentrated in vacuo. Theresulting material was purified in two batches by reversed phasechromatography (15-95% ACN in water (with 0.5 ml/l NH₄OH) over 20 min at50 ml/min, 30×100 mm Phenomenex Gemini C18 column). Desired fractionswere combined and concentrated in vacuo. HRMS [M+H]1+ 450.3099. ¹H NMR(400 MHz, CDCl₃): δ 7.62-7.55 (m, 3 H); 7.42 (d, J=8.5 Hz, 1 H); 7.29(t, J=7.6 Hz, 1 H); 4.44 (s, 2 H); 3.80 (s, 3 H); 2.99 (d, J=10.0 Hz, 1H); 2.85 (d, J=10.2 Hz, 1 H); 2.53 (t, J=7.9 Hz, 1 H); 2.47-2.35 (m, 4H); 2.09-1.92 (m, 5 H); 1.92-1.64 (m, 14 H); 1.28-0.99 (m, 3 H). 210 mg,59%.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation.

Name MS m/z (M + H) N-(1-benzyl-3-methylpyrrolidin-3-yl)-N-[(1- 472.2957methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamide.tert-butyl 4-{(cyclohexylcarbonyl)[(1-methyl-2- 482.3042oxo-1,2-dihydroquinolin-3- yl)methyl]amino}piperidine-1-carboxylateN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 382.2503yl)methyl]-N-piperidin-4- ylcyclohexanecarboxamideN-[1-(cyclopropylmethyl)piperidin-4-yl]-N-[(1- 436.2967methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[1-(cyclobutylmethyl)piperidin-4-yl]-N-[(1- 450.3126methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 396.2653yl)methyl]-N-(1-methylpiperidin-4- yl)cyclohexanecarboxamideN-[1-(cyclopropylcarbonyl)piperidin-4-yl]-N-[(1- 450.2766methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[1-(cyclobutylmethyl)-3-methylpyrrolidin-3-yl]- 450.16N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 368.2335yl)methyl]-N-[(3R)-pyrrolidin-3- yl]cyclohexanecarboxamideN-(1,1-dimethyl-2-piperidin-1-ylethyl)-N-[(1- 438.312methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-(1-benzylpiperidin-4-yl)-N-[(1-methyl-2-oxo- 472.29521,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 382.2484yl)methyl]-N-[(3R)-1-methylpyrrolidin-3- yl]cyclohexanecarboxamideN-[(3R)-1-ethylpyrrolidin-3-yl]-N-[(1-methyl-2- 396.2651oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(3R)-1-(cyclopropylmethyl)pyrrolidin-3-yl]-N- 422.2808[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-cyclopentyl-N-[(1-methyl-2-oxo-1,2- 367.2 dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(3R)-1-acetylpyrrolidin-3-yl]-N-[(1-methyl-2- 410.2462oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamideN-[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]- 436.2628N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(3R)-1-(cyclobutylmethyl)pyrrolidin-3-yl]-N- 436.2978[(1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl]cyclohexanecarboxamide

EXAMPLE 6

(4,4-difluoropiperidin-1-yl)(phenyl)acetonitrile

Benzaldehyde (1.284 ml, 12.63 mmol), 4,4-difluoropiperidine (1.53 g,12.63 mmol), and NaCN (0.619 g, 12.63 mmol) were combined in MeOH (20ml). Acetic acid (0.759 ml, 13.26 mmol) was added dropwise over 30 minvia syringe pump and the mixture heated to reflux for 2 hours. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was partitioned between water and CH₂Cl₂, the aqueousportion extracted 2×CH₂Cl₂, and the organic portion dried (Na₂SO₄) andconcentrated in vacuo. The resulting material was used without furtherpurification.

1-(2-ammonio-1-phenylethyl)-4,4-difluoropiperidinium dichloride

(4,4-difluoropiperidin-1-yl)(phenyl)acetonitrile (500 mg, 2.116 mmol)was dissolved in EtOH (15 ml) and the solution saturated with NH₃ atambient temperature. Raney nickel (1 ml, 2.116 mmol, 50% in water) wasadded and the reaction was put under H₂ balloon pressure for 1.5 hours.Additional Raney nickel (1 ml, 2.116 mmol, 50% in water) was added andthe reaction resubmitted to H₂ for 2 hours. Additional Raney nickel (1ml, 2.116 mmol, 50% in water) was added and the reaction resubmitted toH₂ for 3.5 hours. The reaction mixture was filtered through a 0.45 umsyringe-tip filter, washing with EtOH, and concentrated in vacuo. Thematerial was converted to the corresponding HCl salt by concentratingfrom HCl in ether and carried on crude.

3-({[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]amino}methyl)-1-methylquinolin-2(1H)-one

1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (35 mg, 0.187 mmol),sodium acetate (19.94 mg, 0.243 mmol), and1-(2-ammonio-1-phenylethyl)-4,4-difluoropiperidinium dichloride (51.7mg, 0.187 mmol) were combined in 1,2-dichloroethane (2 ml). Acetic acid(0.021 ml, 0.374 mmol) and sodium triacetoxyborohydride (119 mg, 0.561mmol) were added and the reaction stirred for 1 hour. The reactionmixture was partitioned between CH₂Cl₂ and satd. bicarb, the aqueousportion extracted 3×CH₂Cl₂, and the organic portion dried (Na₂SO₄) thenconcentrated in vacuo. The material was carried on without furtherpurification.

N-[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide

3-({[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]amino}methyl)-1-methylquinolin-2(1H)-one(52 mg, 0.126 mmol), HATU (57.7 mg, 0.152 mmol), cyclohexanecarboxylicacid (0.019 ml, 0.152 mmol), and DIEA (0.026 ml, 0.152 mmol) werecombined in DMF (1.5 ml) and the reaction heated at 50° C. for 0.75hours. The mixture was purified directly by reversed-phasechromatography (15-95% ACN in water (with 0.5 ml/l NH₄OH) over 20 min at20 ml/min, 20×100 mm Phenomenex Gemini C18 column). Fractions containingdesired material were concentrated in vacuo and repurified byreversed-phase chromatography (5-50% ACN (with 0.1% TFA) in water (with0.1% TFA) over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18column). Desired fractions were free-based via Phenomenex Strata X-Ccartridge. HRMS [M+H] 1+ 522.2936. ¹H NMR (400 MHz, CDCl₃): δ 7.60-7.55(m, 1 H), 7.53-7.49 (m, 1 H), 7.39 (d, J=8.52 Hz, 1 H), 7.35-7.28 (m, 4H), 7.25-7.19 (m, 3 H), 4.50-4.35 (m, 2 H), 4.16-4.07 (m, 1 H), 3.88 (t,J=7.6 Hz, 1 H), 3.76 (s, 3 H), 3.31 (dd, J=7.38 Hz, 13.42 Hz, 1 H),2.69-2.65 (m, 2 H), 2.53-2.43 (m, 2 H), 2.28-2.20 (m, 1 H), 2.01-1.88(m, 4 H), 1.74-1.34 (m, 7 H), 1.25-1.05 (m, 3 H). 29.8 mg, 45%.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation.

Name MS m/z (M + H) N-[(1-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-490.6 3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamideN-[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]- 522.2936N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamideN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3- 488.2912yl)methyl]-N-(2-morpholin-4-yl-2- phenylethyl)cyclohexanecarboxamide

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of the formula I:

wherein: R¹is methyl; R² is selected from the group consisting of: (1)tetralone, (2) —CH₂-cyclohexyl, where the cyclohexyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (3)—CH₂-morpholinyl, where the morpholinyl is unsubstituted or substitutedwith one or more substituents selected from R¹³, and (4)—CH₂—CH—(phenyl)heterocycle, where the heterocycle is unsubstituted orsubstituted with one or more substituents selected from R¹³; R³isselected from the group consisting of: (1) —C₁₋₆alkyl, where the alkylis unsubstituted or substituted with one or more substituents selectedfrom R¹³, (2) —C₃₋₆cycloalkyl, where the cycloalkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (3) -phenylor -napthyl, where the phenyl or naphthyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (4)-heterocycle, where the heterocycle is unsubstituted or substituted withone or more substituents selected from R¹³, and (5) —NR¹⁰R¹¹, whereinR¹⁰ and R¹¹are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R¹³,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R¹³, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R¹³, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R¹³, (f)phenyl, which is unsubstituted or substituted with R¹³, and (g)heterocycle, which is unsubstituted or substituted with R¹³; R¹³isselected from the group consisting of: (1) halogen, (2) hydroxyl, (3)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1 (wherein if mis 0 or n is 0, a bond is present) and where the alkyl is unsubstitutedor substituted with one or more substituents selected from R₁₄, (4)—O_(n)—(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, wherethe cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹⁴, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹⁴, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where thephenyl or naphthyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (10) —(C═O)_(m)—NR¹⁵R¹⁶, where R¹⁵ andR¹⁶ are independently selected from hydrogen and —C₁₋₆alkyl, which isunsubstituted or substituted with phenyl, (11) —S(O)₂—NR¹⁵R¹⁶, (12)—S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is —C₁₋₆alkyl, whichis unsubstituted or substituted with phenyl; (13) —CO₂H, (14) —CN, and(15) —NO₂; R¹⁴ is selected from the group consisting of: (1) hydroxyl,(2) halogen, (3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆alkyl, (7) —NH—C₁₋₆alkyl, (8) phenyl, (9) heterocycle, (10)—CO₂H, and (11) —CN; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1 wherein R³ is selected from the group consistingof: cyclohexyl, cyclopentyl, sec-butyl, neo-pentyl and phenyl.
 3. Thecompund of Claim 2 wherein R³ is cyclohexyl.
 4. A compound which isselected from the group consisting of:N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)oxepan-3-yl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[4-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]methyl}cyclohexanecarboxamide;N-({4-[4(1-methylethyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}methyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[4-(4-phenylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]methyl}cyclohexanecarboxamide;N-{[4-(4-benzylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl]methyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-({4-[4-(2-hydroxyethyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}methyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(4-piperazin-1-yltetrahydro-2H-pyran-4-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-({4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]tetrahydro-2H-pyran-4-yl}methyl)cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-N˜2˜-(2,2,2-trifluoroethyl)-L-valinamide;N-[3-methoxy-2-methyl-2-(4-methylpiperazin-1-yl)propyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(3-piperazin-1-yltetrahydro-2H-pyran-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cycloheptanecarboxamide;2-ethyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}butanamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-2-propylpentanamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclopentanecarboxamide;2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}acetamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydrofuran-3-yl]methyl}cyclohexanecarboxamide;N-{[3-(4-methyl-1,4-diazepan-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(2-phenylpiperidin-1-yl)ethyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(2-phenylpyrrolidin-1-yl)ethyl]cyclohexanecarboxamide;N-{2-[benzyl(methyl)amino]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-5-phenyl-1,2-dihydropyridin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;(1S,4R)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}bicyclo[2.2.1]heptane-2-carboxamide;3-methoxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-4-(trifluoromethyl)cyclohexanecarboxamide;2-methyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;4-(1-methylethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;4-tert-butyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;2-cyclohexyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}acetamide;4-methyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}pentanamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl}methyllbenzamide;3-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}propanamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}-2-phenylacetamide;2-cycloheptyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}acetamide;3,3-difluoro-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclopentanecarboxamide;4,4-difluoro-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)tetrahydro-2H-pyran-3-yl]methyl}cyclohexanecarboxamide;N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-benzothiophene-2-carboxamide;N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-3-phenylpropanamide;(1R,2R,4R)-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide;(1S,2S)-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-2-phenylcyclopropanecarboxamide;N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclopropanecarboxamide;3-methyl-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]butanamide;3-cyclopentyl-1-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]urea;N-[(1-morpholin-4-ylcyclohexyl)methyl]-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]1-piperidin-1-ylcyclohexyl)methyl]cyclohexanecarboxamide;N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclobutyl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclopentyl]methyl}cyclohexanecarboxamide;(1R,2R,4R)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclopentyl]methyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide;2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclopentyl]methyl}acetamide;2-(1-hydroxycyclopentyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}acetamide;cis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;cis-4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;trans-4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;N-{[1-(2-methoxyethyl)-2-oxo-1,2-dihydroquinolin-3-yl]methyl}-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-morpholin-4-ylcycloheptyl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-morpholin-4-ylcyclopentyl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-piperidin-1-ylcyclohexyl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-morpholin-4-ylcyclohexyl)methyl]cyclohexanecarboxamide;cis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-piperidin-1-ylcyclohexyl)methyl]cyclohexanecarboxamide;cis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-morpholin-4-ylcyclohexyl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-piperidin-1-ylcyclopentyl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1-morpholin-4-ylcycloheptyl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}cyclohexanecarboxamide;N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)benzamide;3-methyl-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)butanamide;3-tert-butyl-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-(2-phenyl-2-piperidin-1-ylethyl)urea;2-methyl-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzamide;N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-2-phenyl-N-(2-phenyl-2-piperidin-1-ylethyl)acetamide;N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzamide;N-[1-(2-methylphenyl)piperidin-4-yl]-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;3-methyl-N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)butanamide;N-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)thiophene-2-carboxamide;3-(2-chlorophenyl)-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;3-(2-methoxyphenyl)-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;3-cyclopentyl-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-(2-phenyl-2-piperidin-1-ylethyl)urea;3-cyclohexyl-1-[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]-1-(2-phenyl-2-piperidin-1-ylethyl)urea;2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(4-methylpiperazin-1-yl)-2-phenylethyl]acetamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(4-methylpiperazin-1-yl)-2-phenylethyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamide;2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]acetamide;2-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)acetamide;cis-4-(hydroxymethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamide;2-(1-hydroxycyclopentyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)acetamide;cis-4-hydroxy-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamide;N-(1-benzylpiperidin-3-yl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-{4-[2-(4-methylphenyl)ethyl]piperidin-1-yl}ethyl)cyclohexanecarboxamide;N-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(4-benzylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(4-benzylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[3-(2-methylphenyl)pyrrolidin-1-yl]ethyl}cyclohexanecarboxamide;N-{2-[2(1H-indol-2-yl)piperidin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;1-tert-butyl-2-methyl-(2S,4S)-4-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}pyrrolidine-1,2-dicarboxylate;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(2-phenyl-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)ethyl]cyclohexanecarboxamide;benzyl-3-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-phenylpiperidine-1-carboxylate;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-piperidin-1-yl-2-pyridin-3-ylethyl)cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[2-(phenoxymethyl)morpholin-4-yl]ethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]cyclohexanecarboxamide;N-[(3R)-1-(1-methylethyl)pyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(dimethylamino)-1-methylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;benzyl-{2-[(tert-butoxycarbonyl)amino]ethyl}(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}ethyl)carbamate;N-{2-[4-(2,3-dihydro-1H-inden-2-yl)piperazin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;tert-butyl-[(3R,4R)-1-benzyl-4-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}pyrrolidin-3-yl]carbamate;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[4-(phenylcarbonyl)piperazin-1-yl]ethyl}cyclohexanecarboxamide;N-{2-[3-(1,3-benzoxazol-2-yl)piperidin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(4-benzylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(2S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1S,2R)-2-phenylcyclopentyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(3R,4R)-1-methyl-3-phenylpiperidin-4-yl]cyclohexanecarboxamide;N-[2-(3,3-dimethylpiperidin-2-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-y1)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1S,2S)-2-phenylcyclopentyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenylcyclopentyl)cyclohexanecarboxamide;N-[3-(diethylamino)-1,1-dimethylpropyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(1S,9aR)-octahydro-2H-quinolizin-1-ylmethyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1-methyl-3-pyrrolidin-1-ylpropyl)cyclohexanecarboxamide;N-(1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1,1-dimethyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1,1-dimethyl-3-pyrrolidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-(3-phenylpyrrolidin-1-yl)ethyl]cyclohexanecarboxamide;N-[2-(dimethylamino)-2-pyridin-2-ylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[4-(1-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}cyclohexanecarboxamide;tert-butyl-{[1-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}ethyl)piperidin-3-yl]methyl}carbamate;tert-butyl-1-({(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;N-[(3R)-1-(1-methylethyl)pyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{[1-(1-methylethyl)pyrrolidin-2-yl]methyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{[1-(1-methylethyl)pyrrolidin-2-yl]methyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(3S)-1-benzylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-piperazin-1-ylethyl)cyclohexanecarboxamide;N-[(3R)-1-benzylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1,1-dimethyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;tert-butyl-4-(3-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3-methylbutyl)piperazine-1-carboxylate;tert-butyl-4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}ethyl)piperidine-1-carboxylate;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-piperidin-4-ylethyl)cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-(4,4-difluoro-piperidin-1-yl)propyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]tetrahydro-2H-pyran-4-carboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-4,4-difluoro-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]tetrahydro-2H-pyran-3-carboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]tetrahydro-2H-pyran-2-carboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-2-(tetrahydrofuran-3-yl)acetamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-2-(1-hydroxycyclopentyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]acetamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-piperidin-1-ylpropyl)-N-[(1-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-ethyl-1-methyl-3-morpholin-4-ylpropyl)-N-[(1-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2[2-phenylpiperazin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2[4-(cyclopropylmethyl)-2-phenylpiperazin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2[4-(cyclopropylcarbonyl)-2-phenylpiperazin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[4-(cyclobutylmethyl)-2-phenylpiperazin-1-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(4-benzyl-2-phenylpiperazin-1-yl)ethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]cyclohexanecarboxamide;N-[2-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[2-phenyl-2-(tetrahydro-2H-pyran-3-yl)ethyl]cyclohexanecarboxamide;4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino1-1-phenylethyl)-1-(2,2-dimethylpropyl)piperidine;N-[2-(4-hydroxy-1-methylpiperidin-4-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;tert-butyl-4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)-4-hydroxypiperidine-1-carboxylate;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-4-ylethyl)cyclohexanecarboxamide;N-[2-(4-hydroxypiperidin-4-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[4-hydroxy-1-(2-hydroxyethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[1-(1,3-oxazol-5-ylmethyl)piperidin-4-yl]-2-phenylethyl}cyclohexanecarboxamide;N-{2-[1-(2,3-dihydroxypropyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;[4-(2-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidin-1-yl]aceticacid;N-{2-[1-(cyclopropylmethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(2,2-dimethylpropyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(cyclopentylmethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[1-(2-methylpropyl)piperidin-4-yl]-2-phenylethyl}cyclohexanecarboxamide;N-[2-(1-butylpiperidin-4-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(3-methylbutyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(1H-imidazol-2-ylmethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[1-(1,3-oxazol-2-ylmethyl)piperidin-4-y1]-2-phenylethyl}cyclohexanecarboxamide;N-[2-(1-benzylpiperidin-4-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-y1)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(pyridin-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-(2-{1-[(1-methyl-1H-imidazol-2-yl)methyl]piperidin-4-yl}-2-phenylethyl)-N-[(1-methyl-2-oxo1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[1-(1,3-oxazol-4-ylmethyl)piperidin-4-yl]-2-phenylethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(1H-pyrazol-5-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-phenyl-2-[1-(1H-1,2,3-triazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-{2-[1-(cyclopropylmethyl)piperidin-4-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{2-[1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]ethyl}cyclohexanecarboxamide;N-{2-[1-(1H-imidazol-2-ylmethyl)piperidin-4-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(2,2-dimethylpropyl)piperidin-4-yl]ethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(cyclopropylmethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[4-hydroxy-1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[4-hydroxy-1-(1H-imidazol-2-ylmethyl)piperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-{2-[1-(2,2-dimethylpropyl)-4-hydroxypiperidin-4-yl]-2-phenylethyl}-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[1-(cyclobutylmethyl)-3-methylpyrrolidin-3yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-benzyl-3-methylpyrrolidin-3-yl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;tert-butyl-4-{(cyclohexylcarbonyl)[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}piperidine-1-carboxylate;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-piperidin-4-ylcyclohexanecarboxamide;N-[1-(cyclopropylmethyl)piperidin-4-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[1-(cyclobutylmethyl)piperidin-4-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(1-methylpiperidin-4-yl)cyclohexanecarboxamide;N-[1-(cyclopropylcarbonyl)piperidin-4-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[1-(cyclobutylmethyl)-3-methylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(3R)-pyrrolidin-3-yl]cyclohexanecarboxamide;N-(1,1-dimethyl-2-piperidin-1-ylethyl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-(1-benzylpiperidin-4-yl)-N-[1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-[(3R)-1-methylpyrrolidin-3-yl]cyclohexanecarboxamide;N-[(3R)-1-ethylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(3R)-1-(cyclopropylmethyl)pyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-cyclopentyl-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(3R)-1-acetylpyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(3R)-1-(cyclobutylmethyl)pyrrolidin-3-yl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;N-[(1-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)methyl]-N-(2-phenyl-2-piperidin-1-ylethyl)cyclohexanecarboxamide;N-[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide;andN-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-(2-morpholin-4-yl-2-phenylethyl)cyclohexanecarboxamide;or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 6. A method for enhancingthe quality of sleep in a mammalian patient in need thereof whichcomprises administering to the patient a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof.
 7. A method for treating insomnia in a mammalian patient havinginsomnia which comprises administering to the patient a therapeuticallyeffective amount of the compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 8. A method for treating or controlling anxietyin a mammalian patient having anxiety which comprises administering tothe patient a therapeutically effective amount of the compound of claim1 or a pharmaceutically acceptable salt thereof.